Abstract While a heightened risk of seizures in Alzheimer?s Disease (AD) has been observed in sporadic studies from the 1980s to the present, the extent of comorbidity, and the implications for seizures to influence AD progression and outcomes is only now coming to be appreciated. While in the general population, the risk of epilepsy is ~1%, some studies have found the risk in AD to be up to 8-10%. The goal of the parent grant is to understand the circuit mechanisms by which neuromodulation in the basal ganglia can control seizures, with the ultimate goal of identifying new deep brain stimulation targets for epilepsy, such as the deep and intermediate layers of the superior colliculus (DLSC). While a small, but growing, number of studies have evaluated pharmacotherapy as an intervention for seizures in AD models, none, to the best of our knowledge have employed brain stimulation approaches, representing a gap in knowledge. The proposed supplement aims to address this gap in knowledge through two aims. In Aim 1, we will test the hypothesis that open and closed-loop optogenetic activation of the superior colliculus will suppress spontaneous non-convulsive seizures in the TgF344-AD rat model of AD. This represents one of the two major seizure types seen in patients with AD. In Aim 2, we will address the other major seizure type, temporal lobe (limbic) seizures. We will test the hypotheses that TgF344-AD rats will display enhanced limbic epileptogenesis after status epilepticus, that FgF344-AD rats will display more severe impairments in cognition after status epilepticus, and that spontaneous seizures after status epilepticus will be reduced by optogenetic stimulation of the DLSC. Through these aims, we will determine if a promising preclinical brain stimulation approach will also be useful against seizures in a model of AD, determine how AD pathology and cognitive dysfunction are impacted by an epileptogenic insult, and model both of the major seizure types observed in patients with AD.